Ligation of the T cell antigen receptor (TcR) does not result in a single series of events but rather can lead to a wide variety of different outcomes including proliferation, cytotoxicity, apoptosis, distinct patterns Of lymphokine secretion, and anergy. The precise mechanisms responsible for regulating these different outcomes remain unclear. One molecule important in regulating T cell activation is CD45, a family of high molecular weight transmembrane glycoproteins consisting of a cytoplasmic tail containing protein tyrosine phosphatase activity, and a variable external domain encoded in three exons which are differentially expressed due to post-transcriptional alternative RNA splicing, resulting in the expression of at least eight different isoforms. CD45 isoform expression on T lymphocytes is differentially regulated during thymic development and peripheral T cell activation and differentiation, and correlates with distinct effector functions. This suggests the hypothesis that the ectodomain of CD45 can regulate T cell signaling pathways during antigen activation. In support of this hypothesis is the observation that cells that express low molecular weight CD45 isoforms exhibit increased responsiveness to antigen signaling compared to cells expressing high molecular weight isoforms, and that this correlates with the ability of individual low molecular weight CD45 isoforms to associate with the CD4/T cell receptor complex. We hypothesize that the different ectodomain isoforms of CD45 may regulate substrate access to the tyrosine phosphatase domains by targeting CD45 to distinct areas in the membrane where it can associate with other molecules important in T cell signal transduction, altering their phosphorylation status and modifying the TcR signal transduction pathway. Using a combination of biochemical and genetic approaches in transfected T cell lines and in primary CD4 T cells, the investigator will address the following issues in this proposal: 1. The regulation and mechanism of CD45 association with the T cell receptor complex; and 2. The biochemical and biological consequences of CD45 association with the T cell receptor. Increased understanding of the role of CD45 in T cell activation has direct application to the different functional characteristics of naive, memory and effector T cell subsets as well as the changes in T cell function associated with aging. In addition basic studies on the regulation of T cell activation have broad applicability to fields of cancer pathogenesis, autoimmunity, and infectious disease.